Beta-catenin and Androgen Signaling in Prostate Cancer

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BB Principal Investigator/Program Director (Last, first, middle): SUN, ZIJIE DESCRIPTION. State the application's broad, long-term objectives and specificaims, making reference to the health relatedness ofthe project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This description is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXC E E D T H E S PA C E P R O V l D E D. Like most other cancers, prostate carcinogenesis involves a multistep progression from precancerous cells to cells that proliferate locally in an unregulated fashion and then metastasize. During the metastatic phase of this illness tumor cells often lose cell-cell contact and possess a more aggressive growth phenotype. Observations from androgen ablation treatment of prostate cancer have shown that the androgen-signaling pathway is important in the growth and progression of prostate cancer. The growth-promoting effects of androgen are mediated mostly through the androgen receptor (AR). Loss of E-cadherin from the cell membrane is frequently observed in the late stages of prostate cancer, which is closely associated with the increased invasive behavior of tumor cells and a poor clinical outcome. _-catenin, normally localized in the cell membrane, in the cytoplasm and in the nucleus, plays dual roles in intercellular adhesion and signal transduction. Recently, we demonstrated a specific protein-protein interaction between l_-catenin and AR. Unlike the steroid receptor cofactor 1 (SRC1), _-catenin selectively binds to AR in a ligand-dependent manner, but does not bind to other steroid hormone receptors. The interaction domains between AR and [3-catenin are mapped to the ligand binding domain of AR and the N-terminus and central region spanning the armadillo repeats 1-6 of [3- catenin. Through this specific interaction, [3-catenin augments the ligand-dependent activity of AR in prostate cancer cells. These data suggest that _-catenin is a coactivator of the AR and may play a critical role in AR mediated cell growth and survival. Based on the evidence that loss of E-cadherin expression is frequently observed in the advanced stages of prostate cancer, we propose that reduced expression of E-cadherin can elevate the cellular levels of _-catenin in prostate cancer cells, which may directly contribute to the invasiveness and more malignant tumor phenotype by augmenting AR activity in prostate cancer cells. Our major objective in this proposal is to further characterize the interaction between AR and _-catenin in order to understand the biological roles of [3-catenin and its crosstalk with androgen signaling in the tumorigenesis of prostate cancer. Ultimately, we wish to identify the key regions for the interaction (Aim 1), determine the biological roles of _-catenin and its interaction with AR in prostate cancer cells (Aim 2), and define physiological significance of [3-catenin and its regulation in the pathogenesis of prostate cancer (Aim 3). The long-term goal of this study is to identify new steps that can be targeted for the treatment of prostate cancer. PERFORMANCE SITE ========================================Section End===========================================